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l-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study

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Lipids

Abstract

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. l-Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of l-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive l-carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the l-carnitine/simvastatin group [−19.4%, from 52 (20–171) to 42 (15–102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [−6.7%, from 56 (26–108) to 52 (27–93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B and TAG were observed in both groups. Co-administration of l-carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.

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Abbreviations

ALT:

Alanine aspartate aminotransferase

ANCOVA:

Analysis of covariance

apo:

Apolipoprotein

AST:

Aspartate aminotransferase

ATP:

Adenosine triphosphate

CETP:

Cholesteryl ester transfer protein

CK:

Creatine phosphokinase

eGFR:

Estimated glomerular filtration rate

HDL-C:

High-density lipoprotein cholesterol

HOMA:

Homeostasis model assessment

LDL-C:

Low-density lipoprotein cholesterol

LDL-Ccor:

LDL-C levels corrected for Lp(a) concentration

Lp(a):

Lipoprotein (a)

MDRD:

Modification of diet in renal disease

PCSK9:

Proprotein convertase subtilisin/kexin type 9

SD:

Standard deviation

T2DM:

Type 2 diabetes mellitus

TC:

Total cholesterol

TAG:

Triacylglycerol

TSH:

Thyroid stimulating hormone

ULN:

Upper limit of normal

References

  1. Collaboration Cholesterol Treatment Trialists, Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A (2015) Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385:1397–1405

    Article  Google Scholar 

  2. Marcovina SM, Albers JJ (2016) Lipoprotein (a) measurements for clinical application. J Lipid Res 57:526–537

    Article  CAS  PubMed  Google Scholar 

  3. Kronenberg F, Utermann G (2013) Lipoprotein(a): resurrected by genetics. J Intern Med 273:6–30

    Article  CAS  PubMed  Google Scholar 

  4. Tsimikas S, Hall JL (2012) Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol 60:716–721

    Article  CAS  PubMed  Google Scholar 

  5. Kronenberg F (2016) Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 30:87–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Enkhmaa B, Anuurad E, Berglund L (2016) Lipoprotein (a): impact by ethnicity and environmental and medical conditions. J Lipid Res 57:1111–1125

    Article  CAS  PubMed  Google Scholar 

  7. Banach M (2016) Lipoprotein (a)—we know so much yet still have much to learn. J Am Heart Assoc 5(4). doi:10.1161/JAHA.116.003597

  8. Galvano F, Malaguarnera M, Vacante M, Motta M, Russo C, Malaguarnera G, D’Orazio N, Malaguarnera L (2010) The physiopathology of lipoprotein (a). Front Biosci (Schol Ed) 2:866–875

    Google Scholar 

  9. Kotani K, Serban MC, Penson P, Lippi G, Banach M (2016) Evidence-based assessment of lipoprotein(a) as a risk biomarker for cardiovascular diseases—Some answers and still many questions. Crit Rev Clin Lab Sci 53:370–378

    Article  CAS  PubMed  Google Scholar 

  10. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus P (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31:2844–2853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–423

    Article  Google Scholar 

  12. Forbes CA, Quek RG, Deshpande S, Worthy G, Wolff R, Stirk L, Kleijnen J, Gandra SR, Djedjos S, Wong ND (2016) The relationship between Lp(a) and CVD outcomes: a systematic review. Lipids Health Dis 15:95

    Article  PubMed  PubMed Central  Google Scholar 

  13. Malaguarnera M, Vacante M, Russo C, Malaguarnera G, Antic T, Malaguarnera L, Bella R, Pennisi G, Galvano F, Frigiola A (2013) Lipoprotein(a) in cardiovascular diseases. Biomed Res Int 2013:650989

    PubMed  Google Scholar 

  14. Thanassoulis G (2016) Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis. J Lipid Res 57:917–924

    Article  CAS  PubMed  Google Scholar 

  15. Malaguarnera G, Gagliano C, Bucolo C, Vacante M, Salomone S, Malaguarnera M, Leonardi DG, Motta M, Drago F, Avitabile T (2013) Lipoprotein(a) serum levels in diabetic patients with retinopathy. Biomed Res Int 2013:943505

    PubMed  PubMed Central  Google Scholar 

  16. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S, Danesh J (2010) Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 55:2160–2167

    Article  CAS  PubMed  Google Scholar 

  17. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, Consortium P (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361:2518–2528

    Article  CAS  PubMed  Google Scholar 

  18. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus P (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 34:3478–3490a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Irudayam J, Sivaraj S, Nirmala P (2014) Effect of statins on lipoprotein (a) in dyslipidemic patients. Int J Basic Clin Pharmacol 3:1024–1029

    Article  Google Scholar 

  20. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA (2014) Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 63:1278–1288

    Article  CAS  PubMed  Google Scholar 

  21. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, Burkey JL, Yang Q, Marcovina SM, Geary RS, Crooke RM, Witztum JL (2015) Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386:1472–1483

    Article  CAS  PubMed  Google Scholar 

  22. Nicholls SJ, Ruotolo G, Brewer HB, Wang MD, Liu L, Willey MB, Deeg MA, Krueger KA, Nissen SE (2016) Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients. J Clin Lipidol 10(519–527):e514

    Google Scholar 

  23. Serban MC, Sahebkar A, Mikhailidis DP, Toth PP, Jones SR, Muntner P, Blaha MJ, Andrica F, Martin SS, Borza C, Lip GY, Ray KK, Rysz J, Hazen SL, Banach M (2016) Impact of l-carnitine on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of randomized controlled trials. Sci Rep 6:19188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li KM, Wilcken DE, Dudman NP (1994) Effect of serum lipoprotein(a) on estimation of low-density lipoprotein cholesterol by the Friedewald formula. Clin Chem 40:571–573

    CAS  PubMed  Google Scholar 

  25. Galvano F, Volti GL, Malaguarnera M, Avitabile T, Antic T, Vacante M (2009) Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus. Expert Opin Pharmacother 10:1875–1882

    Article  CAS  PubMed  Google Scholar 

  26. Solfrizzi V, Capurso C, Colacicco AM, D’Introno A, Fontana C, Capurso SA, Torres F, Gadaleta AM, Koverech A, Capurso A, Panza F (2006) Efficacy and tolerability of combined treatment with l-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus. Atherosclerosis 188:455–461

    Article  CAS  PubMed  Google Scholar 

  27. Maebashi M, Kawamura N, Sato M, Imamura A, Yoshinaga K (1978) Lipid-lowering effect of carnitine in patients with type-IV hyperlipoproteinaemia. Lancet 2:805–807

    Article  CAS  PubMed  Google Scholar 

  28. Brescia F, Balestra E, Iasella MG, Damato AB (2002) Effects of combined treatment with simvastatin and l-carnitine on triglyceride levels in diabetic patients with hyperlipidaemia. Clin Drug Investig 22:23–28

    Article  CAS  PubMed  Google Scholar 

  29. Sirtori CR, Calabresi L, Ferrara S, Pazzucconi F, Bondioli A, Baldassarre D, Birreci A, Koverech A (2000) l-Carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutr Metab Cardiovasc Dis 10:247–251

    CAS  PubMed  Google Scholar 

  30. Derosa G, Cicero AF, Gaddi A, Mugellini A, Ciccarelli L, Fogari R (2003) The effect of l-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clin Ther 25:1429–1439

    Article  CAS  PubMed  Google Scholar 

  31. McTaggart F, Jones P (2008) Effects of statins on high-density lipoproteins: a potential contribution to cardiovascular benefit. Cardiovasc Drugs Ther 22:321–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hasvold P, Thuresson M, Sundstrom J, Hammar N, Kjeldsen SE, Johansson G, Holme I, Bodegard J (2016) Association between paradoxical HDL cholesterol decrease and risk of major adverse cardiovascular events in patients initiated on statin treatment in a primary care setting. Clin Drug Investig 36:225–233

    Article  CAS  PubMed  Google Scholar 

  33. Power RA, Hulver MW, Zhang JY, Dubois J, Marchand RM, Ilkayeva O, Muoio DM, Mynatt RL (2007) Carnitine revisited: potential use as adjunctive treatment in diabetes. Diabetologia 50:824–832

    Article  CAS  PubMed  Google Scholar 

  34. Malaguarnera M, Vacante M, Avitabile T, Cammalleri L, Motta M (2009) l-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes. Am J Clin Nutr 89:71–76

    Article  CAS  PubMed  Google Scholar 

  35. Malaguarnera M, Vacante M, Motta M, Li Volti G, Galvano F (2009) Effect of l-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus patients treated with simvastatin. Metabolism 58:1618–1623

    Article  CAS  PubMed  Google Scholar 

  36. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Avitabile T, Volti GL, Galvano F (2010) l-Carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis—a randomized and controlled clinical trial. Am J Gastroenterol 105:1338–1345

    Article  CAS  PubMed  Google Scholar 

  37. Elisaf M, Bairaktari E, Katopodis K, Pappas M, Sferopoulos G, Tzallas C, Tsolas O, Siamopoulos KC (1998) Effect of l-carnitine supplementation on lipid parameters in hemodialysis patients. Am J Nephrol 18:416–421

    Article  CAS  PubMed  Google Scholar 

  38. Schmidt K, Noureen A, Kronenberg F, Utermann G (2016) Structure, function, and genetics of lipoprotein (a). J Lipid Res 57:1339–1359

    Article  CAS  PubMed  Google Scholar 

  39. Chang B, Nishikawa M, Nishiguchi S, Inoue M (2005) l-Carnitine inhibits hepatocarcinogenesis via protection of mitochondria. Int J Cancer 113:719–729

    Article  CAS  PubMed  Google Scholar 

  40. Rajasekar P, Anuradha CV (2007) l-Carnitine inhibits protein glycation in vitro and in vivo: evidence for a role in diabetic management. Acta Diabetol 44:83–90

    Article  CAS  PubMed  Google Scholar 

  41. Riches K, Porter KE (2012) Lipoprotein(a): cellular effects and molecular mechanisms. Cholesterol 2012:923289

    Article  PubMed  PubMed Central  Google Scholar 

  42. Boffa MB, Koschinsky ML (2016) Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 57:745–757

    Article  CAS  PubMed  Google Scholar 

  43. Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K, Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M, Lipid, and Blood Pressure Meta-analysis Collaboration G (2015) Tibolone decreases lipoprotein(a) levels in postmenopausal women: a systematic review and meta-analysis of 12 studies with 1009 patients. Atherosclerosis 242:87–96

    Article  CAS  PubMed  Google Scholar 

  44. Sahebkar A, Serban C, Ursoniu S, Banach M (2016) Effect of garlic on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of randomized controlled clinical trials. Nutrition 32:33–40

    Article  CAS  PubMed  Google Scholar 

  45. Dinicolantonio JJ, Niazi AK, McCarty MF, Lavie CJ, Liberopoulos E, O’Keefe JH (2014) l-Carnitine for the treatment of acute myocardial infarction. Rev Cardiovasc Med 15:52–62

    PubMed  Google Scholar 

  46. Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, Org E, Wu Y, Li L, Smith JD, Tang WH, DiDonato JA, Lusis AJ, Hazen SL (2014) γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of l-carnitine to TMAO. Cell Metab 20:799–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL (2013) Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, Lusis AJ, Shih DM (2016) Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 5(2). doi:10.1161/JAHA.115.002767

  49. Skagen K, Troseid M, Ueland T, Holm S, Abbas A, Gregersen I, Kummen M, Bjerkeli V, Reier-Nilsen F, Russell D, Svardal A, Karlsen TH, Aukrust P, Berge RK, Hov JE, Halvorsen B, Skjelland M (2016) The carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis. Atherosclerosis 247:64–69

    Article  CAS  PubMed  Google Scholar 

  50. Collins HL, Drazul-Schrader D, Sulpizio AC, Koster PD, Williamson Y, Adelman SJ, Owen K, Sanli T, Bellamine A (2016) l-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE(−/− transgenic mice expressing CETP. Atherosclerosis 244:29–37

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Medical School, University of Ioannina, 45110, Ioannina, Greece

    M. Florentin, M. S. Elisaf, C. V. Rizos & E. N. Liberopoulos

  2. Department of Cardiology, “Korgialenio Benakio-HRC” Hospital, Athens, Greece

    V. Nikolaou

  3. Lipid Outpatient Clinic, “Tzaneio” General Hospital of Piraeus, Piraeus, Greece

    E. Bilianou

  4. First Cardiology Clinic, School of Medicine, University of Athens, Athens, Greece

    C. Pitsavos

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  1. M. Florentin
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  2. M. S. Elisaf
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Correspondence to M. S. Elisaf.

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Florentin, M., Elisaf, M.S., Rizos, C.V. et al. l-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study. Lipids 52, 1–9 (2017). https://doi.org/10.1007/s11745-016-4216-z

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